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Combination Drug Therapy Does Not Help Migraine Sufferers, New Study Finds

Chronic migraine sufferers who aren't helped by topiramate alone do not fare any better when the beta-blocker propranolol is added to their regimen, according to a study in the Feb. 29 online edition of Neurology.

Researchers halted a double-blind randomized clinical trial that compared the combination of topiramate and propranolol with topiramate plus placebo after it became obvious that the combo treatment wasn't helping to reduce the occurrence of migraine.

“We found that the combination of topiramate with propranolol did not improve average days of moderate-to-severe headache or headache with any severity over a 6-month period,” the investigators reported.

The clinical trial — which was funded by the NINDS and conducted through the NINDS Clinical Research Collaboration, a consortium of community practice-based and university neurologists and physicians — was halted by its data and safety monitoring board not because of safety concerns, but because it was unlikely that continuing the study would result in any significant benefit to participants.

ARE TWO BETTER THAN ONE?

“Physicians often use drugs in combination in the absence of evidence,” Stephen D. Silberstein, MD, professor of neurology at Thomas Jefferson University and the study's principal author, told Neurology Today. He noted that it was a reasonable assumption going into the clinical trial that “since each drug works, they might be even better together.”

“I was surprised that it didn't work,” Dr. Silberstein said. But he noted that while the study ended with a disappointing conclusion, it was nonetheless important to disseminate the results of research that rules out treatment approaches that aren't beneficial.

EPISODIC VS. CHRONIC MIGRAINE

The investigators noted in the paper that topiramate is an effective and well-tolerated medication for episodic migraine. “It is also one of the few preventive treatments for CM [chronic migraine] that has been studied in placebo-controlled, randomized trails with positive significant results,” the researchers wrote. “However, topiramate alone is not an entirely effective CM treatment for most patients; thus combinations of preventive medication are often used.”

The researchers said they considered various combination options before settling on propranolol hydrochloride as the second medication “because it is a standard preventive medication for episodic migraine, represents a different class of medication, has a reasonable side effect profile, is approved by FDA for the prevention of episodic migraine, and has been used in combination with topiramate in an uncontrolled study.”

Participants, who were at least 18 years old, had a history of at least three months of CM as defined by the International Headache Society, and had been able to tolerate at least 50 mg of topiramate daily.

The plan was to randomize 250 patients whose chronic migraines were inadequately controlled with 50 to 100 mg of topiramate daily to either an add-on of 240 mg of propranolol LA (long-acting), 240 mg daily, or a placebo. The primary outcome was 28-day moderate-to-severe headache rate (headache of at least moderate intensity lasting four hours or more, or treated by triptans or ergots regardless of severity or duration) at six months compared to baseline.

The data and safety monitoring board did an interim analysis at the point when 48 participating sites had randomized 171 subjects. The board determined that it would be highly unlikely that the combo therapy would prove useful.

An analysis of results from 191 patients at six months showed that the average reduction in the moderate-to-severe 28-day headache rate for combination therapy was 4.0 days compared to 4.5 days for topiramate alone. The average reduction in the total 28-day headache rate was 6.2 days for the combination therapy compared to 6.1 days for topiramate; none of the differences between the two groups were statistically significant.

EXPERTS COMMENT

Deborah I. Friedman, MD, MPH, a headache medicine specialist who is professor of neurology and neurotherapeutics at the University of Texas Southwestern, said she found the negative results “surprising because propranolol is one of the medications that are considered a class I (evidence) preventive treatment for migraine.” She said that when a single therapy doesn't do enough for patients, doctors might try a combination approach “to attack the problem from different directions.”

“Taking two medications that are useful on their own, that have different mechanisms of action, might give you better outcomes,” said Dr. Friedman, who chairs the AAN Section on Headache and Facial Pain. It is interesting that therapies that are effective for episodic migraines don't necessarily work as preventive medicine for chronic migraine, she added. “There are probably changes in the brain,” in the case of CM, “that are not present in patients with episodic migraines,” she said.

Joel Saper, MD, clinical professor of neurology at Michigan State University, told Neurology Today that because there is no single drug that routinely benefits all patients with migraines, “it's very common for those of us who treat the most difficult of the headache population to look to these combination therapies. Unfortunately, in this case it didn't work.”

Still, Dr. Saper stressed that the negative results of the topiramate-propranolol study should not discourage research into other combinations of treatment. He said there are likely yet undetermined ways to treat migraine because there are many potential targets — neurotransmitters, receptors, nerve cell channels — to focus therapies on. “It is a very complex disorder involving a cascade of physiological events in the brain,” he said, and the path to migraine might be different for different patients.

Dr. Saper, who is also director of the Michigan Head-Pain and Neurological Institute in Ann Arbor, said migraine sufferers already are benefiting from a multi-faceted approach to treatment planning.

“Care is getting better, there are better-care systems in place,” he said. Doctors are no longer looking at migraine in isolation. They're also taking comorbid conditions, such as depression and obesity, into the treatment equation.

According to this latest study, about 2 to 3 percent of adults have chronic migraine. Dr. Silberstein stressed that more research into potential treatments for migraine is critical because the disorder is debilitating and “most drugs only work in 50 to 60 percent of patients.”

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